Suppressive effects of retinoids on iron-induced oxidative stress in the liver.
OBJECTIVE
We previously reported that impaired retinoid signaling in the liver causes steatohepatitis and hepatocellular carcinoma. Recently, oxidative stress induced by hepatic iron overload has emerged as an important factor for the progression of liver disease in patients with chronic hepatitis C, alcoholic liver disease, and nonalcoholic steatohepatitis. In this study, the relationship between retinoid signaling and iron metabolism in the liver was investigated.


METHODS
The effect of retinoids on the iron metabolism was examined in HuH7 cells treated with all-trans retinoic acid and acyclic retinoid NIK-333. In in vivo experiments, we used the mice expressing the dominant negative form of retinoic acid receptor alpha gene under the control of albumin enhancer/promoter (RAR-E Tg) and iron-overloaded wild mice fed with retinoid-deficient and retinoid-excess diets.


RESULTS
Hepatic iron accumulation and increased expression of hemojuvelin were observed in RAR-E Tg mouse liver. Retinoid treatment significantly suppressed expression of hemojuvelin and mildly suppressed expression of transferrin receptor type 2 and hepcidin, accompanied by decreased hepatic iron content and iron-induced oxidative stress in vitro and in vivo. Overexpression of hemojuvelin in HuH7 hepatoma cells led to a significant increase in cellular iron content.


CONCLUSIONS
Our results suggest that retinoids are involved in hepatic iron metabolism through transcriptional regulation of hemojuvelin. This study demonstrated a novel functional role of retinoids in preventing iron-induced oxidative stress in the liver.
Tsuchiya
Hiroyuki
H
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan. tsuchiya@med.tottori-u.ac.jp
Akechi
Yuji
Y
Ikeda
Remina
R
Nishio
Ren
R
Sakabe
Tomohiko
T
Terabayashi
Kei
K
Matsumi
Yoshiaki
Y
Ashla
An Afida
AA
Hoshikawa
Yoshiko
Y
Kurimasa
Akihiro
A
Suzuki
Takao
T
Ishibashi
Naoto
N
Yanagida
Shingo
S
Shiota
Goshi
G
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology; D027682:Cation Transport Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D019698:Hepatitis C, Chronic / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000502:physiology; D011990:Receptors, Transferrin / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011990:Receptors, Transferrin; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C503640:TFR2 protein, human; D000098742:Ferroportin; D007501:Iron